Glioblastoma multiforme (GBM), the most common primary brain cancer, has a 5-year survival rate of only 12%. Poor outcomes are commonplace for GBM patients because chemotherapeutic drugs reach the brain in very low concentrations due to the blood brain barrier (BBB). Biodegradable polymer implants and convection-enhanced delivery approaches circumvent the BBB, but they have only led to moderate improvements in survival. Fortunately, recent clinical trials for GBM with the anti-angiogenesis drug bevacizumab (humanized anti-VEGF IgG) have shown promise, leading to its approval by the FDA for GBM treatment. However, it is also well known that IgG molecules (~150 kD M.W.) do not easily pass through the BBB, suggesting that current bevacizumab treatment is far from optimal. In this proposal, we aim to improve GBM treatment with bevacizumab through the development of an innovative image guided approach that will permit BBB opening to IgG molecules in well-defined locations. Pulsed 1 MHz focused ultrasound (FUS) will be applied to MR-targeted GBMs following the intravenous administration of ultrasound contrast agent microbubbles (MBs). Our pilot studies indicate that the activation of MBs with 1 MHz FUS leads to sonoporation of the BBB without mechanical or thermal damage. We will use 2 specific aims to develop this approach. All studies will use rnu/rnu nude rats with intracranial human Hs683 tumor xenografts.
In Aim 1, for given MB diameters, we will define lower FUS pressure thresholds at which the BBB opens to gadolinium and upper FUS pressure thresholds at which thermal tissue injury and/or microvessel damage may begin to occur. These FUS pressure thresholds will then be used as guides for determining optimal FUS and MB diameter parameters for delivering fluorescent tracer IgG molecules across the BBB to Hs683 tumors.
In Aim 2, these optimal FUS and MB parameters will be used to determine whether the targeted delivery of bevacizumab to intracranial brain tumors with MR-guided FUS and MBs significantly inhibits tumor growth when compared to standard intravenous administration of the drug. If these pre-clinical studies are successful, we are well positioned for translation to clinical trials. The PI is the Research Director of the UVa FUS Center, which houses InSightec Exablate MR-Guided head and body FUS systems. Our next step for this project would be to verify the safety of the FUS and MB procedures for BBB opening in a large animal model. This would be followed by the initiation of a clinical trial. Clinical trials involving FUS application to the brain have been approved for othr indications at UVa, so there is a clear precedent for translation of his work at our institution.

Public Health Relevance

Chemotherapy is often ineffective when treating brain tumors because the interface between the bloodstream and the brain, which is called the blood-brain barrier, is not permeable to drugs in the bloodstream. We are testing the ability of a new technology, which uses MR imaging and specialized ultrasound equipment to open the blood-brain barrier around brain tumors, to permit the delivery of bevacizumab, which is a drug that inhibits blood vessel growth into tumors, for improved brain cancer treatment.